3-substituted-2-piperidinethiones and homologues thereof

ABSTRACT

THIS INVENTION RELATES TO COMPOUNDS OF THE FORMULA:   HN&lt;(-(CH2)N-C(-R2&#34;)(-R3&#34;)-CS-) THESE COMPOUNDS INHIBIT GASTRIC SECRETION AND ARE USEFUL IN TREATMENT FOR A DIGESTIVE ULCER.   -H, -CH3, PHENYL, PHENYL-CH2-   AND R3&#34; IS SELECTED FROM THE GROUP CONSISTING OF   2-PYRIDYL, PHENYL, 4-(H3C-)-PYRIDYL, -CH2-(2-PYRIDYL),   WHEREIN N IS 3 OR 4, R2&#34; IS SELECTED FROM THE GROUP CONSISTING OF

United States Patent US. Cl. 260-29369 2 Claims ABSTRACT OF THEDISCLOSURE This invention relates to compounds of the formula:

wherein n is 3 or 4, R is selected from the group consisting of and R isselected from the group consisting of H, CH3, Q- and -om:

These compounds inhibit gastric secretion and are useful in treatmentfor a digestive ulcer.

This invention relates to new thioacetamide derivatives and theirpharmaceutically acceptable salts which posses an inhibiting activity ona gastric secretion and which are useful in therapeutic andprecautionary treatment for a digestive ulcer, processes for preparingthe same and a composition thereof.

The thioacetamide derivatives can be represented by the followinggeneral formula:

R1 R4 Rz--C-N R: S R&

wherein R is a heterocyclic radical, R is an aralkyl or heterocyclicradical or a lower alkyl radical substituted with a heterocyclicradical, and R R and R are each hydrogen atom; or R is a heterocyclicradical, R and R are both lower alkyl radicals which are linked togetherdirectly to form a 3- to 7-membered saturated ring, and R, and R areeach hydrogen atom; or R and R are both lower alkyl radicals which arelinked together directly to form a thiolactam ring, R is a heterocyclicor aryl radical or a lower alkyl radical substituted with a heterocyclicradical, R is a lower alkyl, aryl or aralkyl radical or a hydrogen atom,and R is a lower alkyl, aryl or aralkyl radical or a hydrogen atom; or Rand R bound together represent a condensed heterocyclidene radical, andR R and R are each hydrogen atom.

The heterocyclic and condensed heterocyclidene radicals in the aboveformula contain at least one nitrogen atom as a hetero atom and mayfurther contain hetero atom(s) selected from nitrogen, oxygen and sulfuratoms.

As a suitable heterocyclic radical in the above formula there may bementioned, for example, an unsaturated heteromonocyclic radicalcontaining nitrogen atom (s) (e.g., pyridyl, pyrazinyl, pyrimidinyl,pyridazinyl,

pyrrolyl, imidazolyl, pyrazolyl, etc.), unsaturated heterodicyclicradical containing nitrogen atom(s) (e.g. indolizinyl, isoindolyl,indolyl, indazolyl, benzimidazolyl, puriny1,isoquinolyl, quinolyl,etc.), unsaturated heteromonocyclic radical containing nitrogen atom(s)and a sulfur atom (e.g. thiazolyl, thiadiazolyl, isothiazolyl,thiatriazolyl, etc.) or saturated heteromonocyclic radical containingnitrogen atom(s) and an oxygen atom (e.g. morpholino, etc.).

As a suitable condensed heterocyclidene radical in the above formulathere may be mentioned, for example, a condensed heterocyclidene radicalcontaining nitrogen atom(s), for example,1,2,3,4-tetrahydroisoquinolidene, 5,6,7,8-tetrahydroisoquinolidene,1,2,3,4-tetrahydroquinolidene, 5,6,7,8-tetrahydroquinolidene, indolideneor quinolizinidene radicals.

The aforementioned heterocyclic and condensed heterocyclidene radicalsmay carry one or more appropriate substituents such as a lower alkylradical of not more than 4 carbon atoms, for example, methyl, ethyl,propyl, isopropyl, butyl or isobutyl radical, a lower alkoxy radical ofnot more than 4 carbon atoms, for example, methoxy, ethoxy, propoxy,isopropoxy, butoxy or isobutoxy radical and the like.

As a suitable lower alkyl radical in the above formula they may bementioned, for example, a lower alkyl radical of not more than 6 carbonatoms, and preferably a lower alkyl radical of not more than 4 carbonatoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutylradical and the like.

As a suitable aryl radical in the above formula there may be mentioned,for example, an aryl radical of not more than 10 carbon atoms, forexample, phenyl, xylyl, tolyl radical and the like.

As a suitable aralkyl radical in the above formula there may bementioned, for example, an aralkyl radical of not more than 12 carbonatoms, and preferably an aralkyl radical of 7 to 10 carbon atoms, forexample, benzyl, phenethyl, 3-phenylpropyl, 2-phenylpropyl, xylyl-methylradical and the like.

The aforementioned aryl and aralkyl radicals may carry one or moreappropriate substituents such as a halogen atom (e.g. chlorine, bromine,etc.), a hydroxy radical and the like.

The thioacetamide derivatives of the formula I may be divided into thefollowing classes:

(a) Those having the formula:

wherein R is a heterocyclic or aryl radical or a lower alkyl radicalsubstituted with a heterocyclic radical, R is a lower alkyl, aryl oraralkyl radical or a hydrogen atom, R is a lower alkyl, aryl or aralkylradical or a hydrogen atom, and n is 2, 3 or 4.

It has been found that the thioacetamide derivatives of the formula (I)and their pharmaceutically acceptable salts commonly andcharacteristically possess an inhibiting activity on a gastric secretionbut no anticholinergic and central nervous system effects, and may becharacteristically useful in therapeutic and precautionary treatment fora digestive ulcer.

Accordingly, a basic feature of the present invention is to provide newthioacetamide derivatives of the formula (I) and their pharmaceuticallyacceptable salts.

According to a feature of the invention, there are provided newthioacetamide derivatives of the formula (I) and their pharmaceuticallyacceptable salts possessing a selective inhibiting activity on a gastricsecretion and being useful in therapeutic and precautionary treatmentfor a digestive ulcer. According to a further feature of the invention,there may be provided a pharmaceutical composition comprising, as anactive ingredient, new thioacetamide derivatives of the formula (I) andpharmaceutically acceptable carriers as therapeutic and precautionaryagents for a digestive ulcer.

According to a still further feature of the invention, there areprovided processes for preparing new thioacetamide derivatives of theformula (I) and their pharmaceutically acceptable salts. These and otherfeatures of the invention will be apparent to those conversant with theart to which the present invention pertains from the subsequentdescriptions.

The compound (I) of this invention, including the compound (II) and(III) can be prepared by the methods as mentioned below.

The compound of the formula (I) can be prepared by reacting an acetamidederivative of the formula:

s (IV) wherein R is a heterocyclic radical, R is an aralkyl orheterocyclic radical or a lower alkyl radical substituted with aheterocyclic radical, and R R and R are each hydrogen atom; or R is aheterocyclic radical, R and R are both lower alkyl radicals which arelinked together directly to form a 3- to 7-membered saturated ring, andR and R are each hydrogen atom; or R and R are both lower alkyl radicalswhich are linked together directly to form a thiolactam ring, R is aheterocyclic or aryl radical or a lower alkyl radical substituted with aheterocyclic radical, R is a lower alkyl, aryl or aralkyl radical or ahydrogen atom, and R is a lower alkyl, aryl or aralk yl radical or ahydrogen atom; or R and R bound together represent a condensedheterocyclidene radical, and R R and R are each hydrogen atom, with aninorganic sulfide.

3- (2-Pyridyl)-2-piperidone which falls within the scope of the startingcompounds (IV) to be used in the present reaction can be preparedaccording to a manner reported in The Journal of the American ChemicalSociety, volume 81 (1959), page 737, and 3-phenyl-2-piperidone and 1-(alkyl or aralkyl)-3-phenyl-2-piperidone, according to a manner reportedin Chemical Abstracts, volume 45 (1951), column 7154c. The otherstarting compounds (IV) can be prepared according to a manner similar tothose of the said journals.

As a suitable inorganic sulfide to be used in the above reaction theremay be mentioned, for example, phosphorus pentasulfide, sodium sulfide,potassium sulfide, ammonium sulfide, ammonium polysulfide, calciumsulfide, barium sulfide, ferrous sulfide, ferric sulfide and the like.

The present reaction is effected with or without a solvent preferablywith heating. As a suitable solvent there may be mentioned, for example,pyridine, benzene, toluene, xylene, ether, tetrahydrofuran, dioxane andthe like.

The compound of the formula (II) can be prepared by reacting anacetonitrile derivative of the formula:

Rs (V) wherein R is a heterocyclic radical, R is an aralkyl orheterocyclic radical or a lower alkyl radical substituted with aheterocyclic radical and R is a hydrogen atom; or R is a heterocyclicradical, and R and R are both lower alkyl radicals which are linkedtogether directly to form a 3- to 7-membered saturated ring; or R and Rbound together represent a condensed heterocyclidene radical, and R is ahydrogen atom, or an iminoether derived therefrom by addition of analcohol, with an inorganic sulfide.

a-Benzyl-2-pyridineacetonitrile which falls within the scope of thestarting compound (V) to be used in the present reaction can be preparedaccording to a manner reported in Yakugaku Zashi (Japan), volume (1965),

page 812, and the other starting compounds of the present reaction canbe prepared according to a manner similar to that of the said journal.

As a suitable inorganic sulfide used in the above reaction there may bementioned, for example, hydrogen sulfide, phosphorus pentasulfide,sodium sulfide, ammonium polysulfide, potassium sulfide, ammoniumsulfide, calcium sulfide, barium sulfide and the like.

The present reaction is carried out with or without a solvent andpreferably with a solvent. As a suitable solvent there may be mentioned,for example, methanol, ethanol, benzene, toluene, xylene, ether,tetrahydrofuran, dioxane, chloroform, pyridine, dimethylformamide andthe like. There is no limitation to the reaction temperature. However,the reaction is preferably carried out at above room temperature. Thereaction can be preferably carried out in the presence of a base such aspyridine, ammonia, tri ethylamine, triethanolamine, sodium, potassiumand the like.

As stated above, the thioacetamide derivatives (I) and theirpharmaceutically acceptable salts show an inhibiting activity on agastric secretion but no anti-cholinergic and central nervous systemeffects. Some of the test results by which the said activities areevidenced are shown below.

TEST 1 Inhibition of gastric secretion in Shays rats Method: MaleSprague-Dawley J CL strain rats, weighing 200 to 300 g., were used. Fourhours after the pyloric ligation, the animals were killed and theirstomachs were removed. The test compound was administered subcutaneously30 min. before the pyloric ligation. The volume of the gastric fluid wasmeasured and expressed as milliliters per g. of body weight. The meanvolume of animals receiving an equal dose was compared with that of thecontrol. The ED values were calculated.

TABLE 1 Compound: ED'50 (mg/kg.) 3 (2 Pyridyl) 2 piperidinethion hydro-1-(Z-Pyridyl)cyclopentanethioamide 50.0 u-(zPyridyl)-2-pyridinethioacetamide 16.0

TEST 2 Inhibition of gastric secretion in dogs (Fistula method) Method:Mongrel adults dogs, weighing 7-15 kg., were used after a 22 hourdeprivation of food but no water. They were anesthetized with chloralose(50 -mg./ kg.) and urethane (1.5 g./kg.) and a gastric fistula wasprepared in each animal. The prepared animals were tied out on aspecific board, lying prone, and the gastric fluid was estimated forvolume and acidity every 15 minutes. After approximately constant basicexcretion volumes were obtained consecutively some times, the tests weremade. The test compound was administered 60 minutes before a stimulatingdrug of the gastric secretion, gastric tetrapeptide (30 ,ug./h.). The EDvalue was calculated.

TABLE 2 Compound: ED (mg/kg.)

3-(2-Pyridyl)-2-piperidinethione hydrochloride 5.0a-Benzyl-2-pyridinethioacetamide 2.6

TEST 3 Antagonism of histamineand acetylcholine-induced contraction ofthe isolated guinea pig ileum (Magnus technique) Method: Strips ofileum, 2 cm. in length, were removed from male guinea pigs (300-500 g.)and suspended in 50 ml. Tyrodes baths. The temperature of the bath wasmaintained at 27 C. and Tyrodes solution was saturated with a mixture of95% oxygen and 5% carbon dioxide. The contraction of the ileal strip wasrecorded with a strain gauge. The spasmogen employed was acetlycholine(0.2 lg/ml. or histamine phosphate (0.1 ,ug./ ml.). The test compound,3-(2-pyridyl)-2-piperidinethione, was added to the bath one minute priorto addition of the spasmogen. The ED inhibitory concentration wascomputed from the size of the ileal contraction on the graph.

TABLE 3 Spasmogen: so Acetylcholine chloride Inactive Histaminephosphate Inactive TEST 4 Acute toxicity Method: The test compound wassubcutaneously administered to groups of dd-strain male mice, each groupconsisting of, animals. Death was numbered for 2 days after theadministration, and the LD value was calculated according to theLitchfield-Wilcoxon method.

TABLE 4 Compound: LD

0:. Benzyl 2 pyridinethioacetamvide hydrochloride 380 a. Benzyl 2pyridinethioacetamide hydrochloride 480 1,2,3,4 Tetrahydro 1isoquinolylidenethioacetamide 560 This invention is illustrated but notlimited by the following Examples.

EXAMPLE 1 A solution of u-(o-chlorobenzyl)-2-pyridine-acetonitrile (1.5g.) in methanol (20 cc.) with amonium polysulfide wassealed in glasstube and the glass tube was allowed to stand for 2 days. The solvent ofthe reaction mixture was distilled off and the residue was subjected tochromatography over alumina in which a mixed solvent of chloroform andacetone (4:1) was used as a developer. Te solvent of the eluate wasdistilled otf and the residue was recrystallized from ethanol to givecolorless crystals (0.75 g.) ofa-o-chlorobenzyl)-2-pyridinethioacetamide, m.p. 136-138 C.

Analysis-Calculated for C H N SCI: C, 60.75; H, 4.73; N, 10.12; Cl,12.81. Found: C, 60.98; H, 4.66; N, 9.89; Cl, 12.87.

The following compounds were prepared according to a manner similar tothe preceding Example 1.

1 Decomposed.

EXAMPLE 9 Triethylamine (10 cc.) was added to a solution of 6,7-dimethoxy 1,2,3,4 tetrahydro-l-isoquinolylideneacetonitrile (2.2 g.) inpyridine (60 cc.) and the mixture was passed with hydrogen sulfide gasfor 5 hours under stirring. The solvent was distilled off completely byadding water thereto, and to the residue was added water. Precipitateswere collected by filtration, dried and recrystallized from ethanol togive yellowish needles 1.4 g.)

of 6,7-dimethoxy-1,2,3,4-tetrahydro 1 isoquinolylidenethioacetamide,m.p. 168170 C.

Analysis.--Calculated for C H N O S: C, 59.06; H 6.10; N, 10.60; S,12.13. Found: C, 59.10; H, 6.11; N, 10.61; S, 12.30.

EXAMPLE 10 Triethylamine (8 cc.) was added to a solution of 1,2,3,4-tetrahydro 1 isoquinolylideneacetonitrile (2.3 g.) in pyridine (30cc.) and the mixture was passed with hydrogen sulfide gas for 3.5 hoursunder stirring. The solvent was distilled off completely by adding waterthereto and to the residue was added ethanol. The ethanol solution wasconcentrated to dryness, and the residue was subjected to chromatographyover alumina in which a mixed solvent of benzene and ethyl acetate (4:1)was used as a developer. The solvent of the eluate which was obtained inthe latter half was distilled off and the residue was recrystallizedfrom benzene to give yellowish prisms (0.3 g.) of1,2,3,4-tetrahydro-1-isoquinolylidenethioacetamide, m.p. 137.5139.5 C.

Analysis.-Calculated for C H N S: C, 64.67; H, 5.92; N, 13.71. Found: C,64.40; H, 5.85; N, 13.79.

was prepared according to a manner similar to the preceding Example 10.

7 EXAMPLE 12 A Solution of phosphorus pentasulfide (1.86 g.) in pyridine(48 cc.) was added to a solution of 3-(2-pyridyl)-2- piperidone (7.12g.) in pyridine (24 cc.) and the mixture was refluxed for about 2.5hours under stirring. After the completion of the reaction, the mixturewas poured into a hot water (850 cc.) under stirring and allowed tostand. Precipitates were removed by filtration and the filtrate wasextracted six times with ethyl acetate (400 c). The ethyl acetate layerwas dried and the solvent was distilled 011. The residue was subjectedto chromatography in which a mixed solvent of benzene and acetone (2:1)was used as a developer and the solvent of the eluate obtained in thelatter half was distilled off to give crystals (5.47 g.) of3-(2-pyridyl)-2-piperidinethione, m.p. 145- 146 C.

Analysis.-Calculated for C H N S: C, 62.46; H, 6.29; N, 14.57; S, 16.68.Found: C, 62.49; H, 6.27; N, 14.47; S, 16.98.

To a solution of 3-(2-pyridyl)-2-piperidinethione (5.4 g.) in 99%ethanol (80 cc. )was added absolute ether (100 cc.), and the mixture waspassed with dry hydrogen chloride gas. Precipitates were collected byfiltration and washed with a mixed solvent of ethanol and ether (1:2)and then dried. This material was further dissolved in hot 99% ethanol(200 cc.) and the ethanol solution was filtered. To the filtrate wasadded ether (80 cc.) and the mixture was allowed to stand. Precipitateswere collected by filtration and dried to give crystals (4.75 g.) of3-(2- pyridyl)-2-piperidinethione hydrochloride, m.p. 23 3234 C.(decomp.).

AnalysiS.--Calculated for C H N SCl: C, H, 5.73; N, 12.25; S, 14.02; Cl,15.50. Found: C, 52.66; H, 5.72; N, 12.19; S, 13.75;Cl, 15.77.

The following compounds were prepared according to a manner similar tothe preceding Example 12.

8 EXAMPLE 22 Phosphorus pentasulfide 1.0 g.) was added to a solution ofu-(Z-pyridyl)-2-pyridineacetamide (1.0 g.) in pyridine (10 cc.) and themixture was heated on the bath of C. for 1 hours. The solvent of themixture was distilled off and the residue were added water andchloroform, and the chloroform layer was separated and dried. Thechloroform was distilled off and the residue was subjected tochromatography in which a mixed solvent of chloroform and acetone (4: 1)was used as a developer. The solvent of the eluate obtained in thelatter half was distilled off to give, as the residue, crystals (0.4 g.)of oz- (Z-pyridyl)-2-pyridinethioacetamide, m.p. 158-161 C.

Analysis.-Calculated for C H N S: C, 62.85; H, 4.84; N, 18.33. Found: C,63.00; H, 4.69; N, 18.62.

The following compounds were prepared according to a manner similar tothe preceding Example 22.

25 Same as above.-

-OH2- N 2 Free base.

af/L 1 2) J S N H Physicochemical Number Ra" Ra" n 1122 3 5:

14 Same as above f E 3 162-163 1 5 do CH 3 120. 5-121. 5

16 do H 3 1 224-227 18 CH: H 3 257-260 1 Hydrochloride.

TABLEContlnued Physlcoehemiczl pro er y Number R R1 M.P.?O.

26. Sazne as No. 24".-- 139-141 Cl- OH2- CHr- / CH2- N H Y NH l HCH-C-NH:

Physlcochemlcal proper y No; x Y M.P., of

CHQO- 168-170 H H 137-139. 5 33. 1-(2-pyrldyl)eyclopentanethioamide188-189 34- 1,3-dimethyl-3-(2-pyridyl)-2-piperidinethione 76. 5-77 351-benzyl-3-(2-pyridyl)-2-piperldinethione 66-68 361inhiithyl-ii-phenyl-3-(2-pyrldyl)-2-piperidlne- 152153.5

one 37 1-methyl-3-benzyl-3-(2-pyrldyl)-2-plperl- 113-114 dinethione1-benzyl-3-methyl-3-(2-pyridyl)-2-plperi- 84. 5-85. 5 39 1g$% 1 3(2- dl) 2- 1 d1 173-176 5 enzypyri y eri nethione (H01) p p 401-benzyl-3-phenyl-3-(2-pyrldyl)-2-piperl 94-95 'nethlone 41Liildiiphenyl-ii-(lpyridyl)-2-pyrro1idine- 154.5155.5

one

Because of the possession of the said activity, the thioacetarnidederivatives of the formula (I) and their pharmaceutically acceptablesalts are useful as therapeutic and precautionary agents for a digestiveulcer.

The thioacetamide derivatives of the formula (I) and theirpharmaceutically acceptable salts can be administered by theconventional methods, the conventional types of unit dosages or with theconventional pharmaceutical carriers to produce an inhibiting activityon a gastric secretion of human beings.

Thus, they can be used in the form of pharmaceutical preparations, whichcontain them in admixing with a pharmaceutical organic or inorganiccarrier material suitable for enteral or parenteral applications. Oraladministration by the use of tablets, capsules or in liquid form such assuspensions, solutions or emulsions is particularly advantageous. Whenformed into tablets, the conventional binding and disintegrating agentsused in therapeutic and precautionary unit dosages can be employed.Illustrative of binding agents there can be mentioned glucose, lactose,gum acacia, gelatin, mannitol, starch paste, magnesium trisilicate andtalc. Illustrative of disintegrating agents there can be mentioned cornstarch, keratin, colloidal silica and potato starch. When administeredas liquids the conventional liquid carriers can be used.

The unit dosage or therapeutically or precautionally effective quantityof the compounds (I) and their pharmaceutically acceptable salts forhuman beings can vary over wide limits such as that of 0.1 milligram toabout 100 milligrams. The upper limit is limited only by the degree ofelfect desired and economic considerations. For

oral administration it is preferable to employ from about 1 milligram toabout milligrams of the therapeutic or precautionary agent per unitdosage. It is indicated from animal experiments that about 1 to about 10milligrams dosages administered orally four times daily as needed willprovide a preferred daily dosage. Of course, the dosage of theparticular therapeutic or precautionary agent used can varyconsiderably, such as the age of the patient and the degree oftherapeutic or precautionary elfect desired. Each unit dosage form ofthe novel therapeutic and precautionary compounds can contain from about5% to about 9.5% of the novel therapeutic and precautionary agents byweight of the entire composition with the remainder comprisingconventional pharmaceutical carriers. By the term pharmaceutical carrierit is intended to include non-therapeutic materials which areconventionally used with unit dosage and include fillers, diluents,binders, lubricants, disintegrating agents and solvents. Of course, itis possible to administer the novel therapeutics, i.e. the purecompounds, without the use of a pharmaceutical carrier. It is alsopossible to administer the thioacetamide derivatives of the formula (I)and their pharmaceutically acceptable salts in the form of mixture withother agents which are used as therapeutics for a digestive ulcer.

The following examples illustrate the preparation of the composition,but shall not be limited thereto.

Example A.Formula of the tablets are given below:

Formula per tablet Ingredient Potato starch Lactose Spray-dry lactoseAvicel (trademark) Methylcellulose Magensium stearate Potassiumcarboxymethyl cellulose..- Colloidal silicic acid Coated to make...

Example B.Formula of the given below:

Ingredient (per one ampoule):

3 (2 Pyridyl) 2 piperidinethione hydroinjectable solution is chloride5.0 Sodium chloride 9.0 Distilled water for injection to make 1 cc. pH5.0-7.5.

A preferable composition for rectal administration may be suppository,for which bases are exemplified with cacao butter, glycerogelatin,polyvinylalcohol, vegetable hardcued oil and the like.

Example C.--Formula of the suppository is as follows:

Formula per suppository wherein n is 3 or 4, R is selected from thegroup consisting of 3- and Qm 1 1 1 2 and R is selected from the groupconsisting of W. Theilheimer: Synthetic Methods of Organic Chemistry(1952), vol. 96, p. 229. a-. Q- and CH2 W. Theilheimer: SyntheticMethods of Organic Chemistry (1955), vol. 9, p. 238. 2. A compoundaccording to claim 1 m which the thioacetamide compound is3-(2-pyridyi)-2-piperidine- HENRY JILES, Primary Examiner thione.

References Cited S. D. WINTERS, Assistant Examiner UNITED STATES PATENTSl. X. 2,524,643 10/1950 Walter et al 260293.76 10 Us c R 2,742,4754/1956 Hofimann 61; a1. 260 293.69 261F309, 310 C, 310 R, 250 2 2, 306.8D, 256.5 R, 308 R, 247.1, 283 CN, 283 s, 293.68, 293.73, 293.76, OTHERREFERENCES 294.8 E, 294.9, 309.2, 239.3 R; 424248, 258, 263, 267,Medicinal Chemistry, Burger, vol. I (1951), pp. 44, 45, 15 273 48.

P0405!) UNITED STATES PATENT Orrl'CE CERTHJLCPLTE CGRRECTEC-fi PatentNo. 3 823 152 Dated J l 9 1974 inventofls) Akiro Morir noto, et a1.

It is certif' and that said Let In the headnote, at listing of'priorityclaims, after ""July 30,1970, 45/67,049 insert August 18, 1970,45/72,201

in the Abstract of Disclosure, at line 25,- the formula which: reads:

. N O m -cn,- v I l I N I p v is corrected to read as follows: Q

. V n h. Q N Q Q Q In-0011mm 6, in line 2 of Table of Example 1, thetormula which reads 2 usz-lsas ed that error appears in theabove-identified patent ters Patent are hereby corrected as shown below:

is corrected to read as follows: 2 H "mm N HOG-CH!" UNITED STATES PATENTOFFICE Page 2 v CERTIFICATE OF CORRECTION Patent. 5, 5, 5 Dated y 9, 9%

A Inventor) aklro Morlmoto, et 81.

It is certified that error appears in the above-identified patent andthat said Letters Patent are hereby corrected as shown below:

line 18 of thQTable of Example 12, the

In Column 7', in formula which reads:

i 1 I I i W- -w is .corrected to read as follows: Q

Signed and sealed this 11th day of February 1975..

(SEAL) Attest:

Y C. MARSHALL DANN .RUTH C. MASON Commissioner of Patents 'AttestingOfficer and Trademarks FORM 0-1050 (10-69) USCOMM-DC 60375-P59 u.scovzmmzm PRINTING ornc: 1 93 o

